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Transcriptional Control and Signal Transduction

JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma

Leukemia volume 28, pages 338–348 (2014)Cite this article

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Abstract

Extranodal, nasal-type natural killer (NK)/T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. Here, we demonstrate that STAT3 activation mostly results from constitutive Janus kinase (JAK)3 phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples under study. In one of the cell lines and in 4 of 19 (21%) NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. We then show that constitutive activation of the JAK3/STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor CP-690550. Altogether, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL that deserves to be tested as a therapeutic target.

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Acknowledgements

We are indebted to Professor Kaiss Lassoued for invaluable discussions and advice. This work was funded in part by grants from the following institutions: Etablissement Français du Sang (CS/2002/009), GIS-Institut des Maladies Rares (GIS MR0428), Fondation pour la Recherche Médicale (FRM) and Institut National du Cancer (INCA). We also thank Virginie Fataccioli for the management of the TENOMIC program, and Sandrine Malot and Cécile K Lopez for technical assistance, as well as the members of the consortium TENOMIC (cited in Appendix).

Author information

Author notes

  1. L Scourzic, O de Wever, Y Zhang, C Gespach and E Solary: These authors contributed equally to this work.

Authors and Affiliations

  1. Unité Inserm U1009 ‘Hématopoïèse normale et pathologique’,

    A Bouchekioua, Y Zhang, W Vainchenker, F Louache, E Solary & P Coppo

  2. Institut Gustave Roussy, Villejuif, France

    A Bouchekioua, Y Zhang, W Vainchenker, F Louache, E Solary & P Coppo

  3. Université Paris 11, Institut Gustave Roussy, Villejuif, France

    A Bouchekioua, L Scourzic, Y Zhang, T Mercher, W Vainchenker, F Louache & E Solary

  4. Institut Gustave Roussy, Villejuif, France

    A Bouchekioua, L Scourzic, Y Zhang, T Mercher, W Vainchenker, F Louache & E Solary

  5. U938 ‘Cellules souches: application à la thérapie cellulaire hématopoïétique’, Centre de Recherche Saint-Antoine, UPMC University Paris 06, Paris, France

    A Bouchekioua, D Jeziorowska & L Douay

  6. Unité Inserm U985 ‘Génétique des tumeurs’, Institut Gustave Roussy, Villejuif, France

    L Scourzic & T Mercher

  7. Department of Radiotherapy and Nuclear Medicine, Laboratory of Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium

    O de Wever

  8. Service d'Anatomo-pathologie, AP-HP, Hôpitaux Universitaires Paris-Est, UPMC University Paris 06, Paris, France

    P Cervera & A Aline-Fardin

  9. Inserm U955, Créteil, France

    P Gaulard

  10. Université Paris-Est, Créteil, France

    P Gaulard

  11. Département de Pathologie, AP-HP, Hôpital Henri Mondor, Créteil, France,

    P Gaulard

  12. Service d'Immunologie, UFR de Médecine, 3 Rue des Louvels, Amiens, France,

    R Nyga

  13. Unité Inserm U938 ‘Molecular and Clinical Oncology’, UPMC University Paris 06,

    C Gespach

  14. Centre de Référence des Microangiopathies Thrombotiques, Service d’Hématologie, AP-HP, Hôpitaux Universitaires Paris-Est, UPMC University Paris 06, Paris, France

    P Coppo

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  1. A Bouchekioua
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Correspondence to P Coppo.

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Appendix

Appendix

The members of the consortium TENOMIC are:

A Martin, Hôpital Avicenne, Bobigny; I Soubeyran, P Soubeyran, Institut Bergonié, Bordeaux; P Dechelotte, A Pilon, O Tournilhac, Hôtel-Dieu, Clermont Ferrand; K Leroy, P Gaulard, MH Delfau, C Copie-Bergman, A Plonquet, C Haïoun, F Le Bras, Hôpital Henri Mondor, Créteil; T Petrella, L Martin, JN Bastié, O Casasnovas, CHU, Dijon; B Fabre, D Salameire, R Gressin, D Leroux, MC Jacob, CHU, Grenoble; L de Leval, B Bisig, G Fillet, C Bonnet, CHU Sart-Tilman, Liège; MC Copin, B Bouchindhomme, F Morschhauser, CHU, Lille; B Petit, A Jaccard, Hôpital Dupuytren, Limoges; F Berger, B Coiffier, CHU Sud, Lyon; T Rousset, P Quittet, G Cartron, Hôpital Gui de Chauliac-St Eloi, Montpellier; S Thiebault, B Drenou, Hôpital E Muller, Mulhouse; K Montagne, C Bastien, S Bologna, CHU de Brabois, Nancy; C Bossard, S Le Gouill, Hôtel-Dieu, Nantes; T Molina, Hôtel-Dieu, Paris; J Brière, C Gisselbrecht, Hôpital St Louis, Paris; B Fabiani, A Aline-Fardin, P Coppo, Hôpital Saint-Antoine, Paris; F Charlotte, J Gabarre, Hôpital Pitié-Salpétrière, Paris; J Bruneau, D Canioni, V Verkarre, E Macintyre, V Asnafi, O Hermine, R Delarue, F Suarez, D Sibon, JP Jaïs, Hôpital Necker, Paris; M Parrens, JP Merlio, E Laharanne, K Bouabdallah, Hôpital Haut Lévêque, Bordeaux; S Maugendre-Caulet, P Tas, T Lamy, CHU Pontchaillou, Rennes; JM Picquenot, F Jardin, C Bastard, Centre H Becquerel, Rouen; M Peoc′h, J Cornillon, CHU, Saint Etienne; L Lamant, G Laurent, L Oberic, Hôpital Purpan, Toulouse; J Bosq, P Dartigues, V Ribrag, Institut G Roussy, Villejuif; M Patey, A Delmer, Hôpital R Debré, Reims; JF Emile, K Jondeau, Hôpital Ambroise Paré, Boulogne; MC Rousselet, M Hunault, CHU, Angers; C Badoual, Hôpital Européen Georges Pompidou, Paris; C Legendre, F Boidart, S Castaigne, AL Taksin, CH Versailles, Le Chesnay; J Vadrot, A Devidas, B Joly, CH Sud francilien, Corbeil; Dr Gandhi Damaj, CHU Amiens; F Lemonnier, M Travert, INSERM U955, Créteil; P Dessen, G Meurice, Institut G Roussy, Villejuif; M Delorenzi, E Missiaglia, N Houhou, P David, Swiss Institute of Bioinformatics, Lausanne, Switzerland; F Radvanyi, E Chapeaublanc, Institut Curie, Paris; P Ferrier, S Spicuglia, CIML, Marseille; J Soulier, Hôpital St Louis, Paris; C Thibault, IGBMC, Illkirsch. The LYSA (Lymphoma Study Association). Plate-Forme de Ressources Biologiques, Hôpital H Mondor, Créteil. V Fataccioli, Project Manager, Hôpital H Mondor, Créteil.

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Bouchekioua, A., Scourzic, L., de Wever, O. et al. JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. Leukemia 28, 338–348 (2014). https://doi.org/10.1038/leu.2013.157

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